We have demonstrated that ADC serves as a reliable biomarker for differentiating between GS 3 + 4 and 4 + 3 tumors, despite both being classified as GS 7. Patients diagnosed with GS 4 + 3 disease exhibited poorer bDFS and PCSS outcomes compared to those with GS 3 + 4 tumors. While a significant correlation between disease progression and tumor ADC was evident across the entire cohort, a dose-response relationship between ADC and progression was specifically observed in patients with GS 3 + 4 tumors, but not for GS 4 + 3 tumors, underscoring the critical importance of GS upgrading in biopsy specimens. Therefore, ADC may serve as a pivotal tool for discriminating patients at high risk of disease progression, particularly among those diagnosed with GS 3 + 4 tumors.
Previous studies have shown significant differences in the behavior of GS 3 + 4 disease in comparison to GS 4 + 3 disease among patients who underwent RP [2, 3]. However, conflicting findings have been reported for patients undergoing definitive RT [18, 19]. Delahunt et al.[18] demonstrated that GS 3 + 4 and 4 + 3 serves as a significant prognostic indicator for DM and PCa mortality. In contrast, Merrick et al.[19] found that the 5-year biochemical outcomes subsequent to prostate brachytherapy are largely unaffected by whether a GS 7 tumor predominantly exhibits a pattern of 3 + 4 or 4 + 3 histologic features. Discrepancies in treatment outcomes seen in patients receiving definitive RT may be due to differences between the GS obtained from biopsies and the GS determined after RP. Our study highlights the significance of GS 4 + 3 as the primary factor that predicts adverse outcomes in terms of bDFS and PCSS. However, it is crucial to further enhance the precise distinction between GS 3 + 4 and 4 + 3 tumors to improve treatment outcomes.
While transrectal ultrasonography (TRUS)-guided systemic biopsy may not always sample the most aggressive part of PCa, DW-MRI can help locate the cancer and detect the most significant area.[20] Previous studies have suggested that ADC values could be useful in distinguishing between patients with high- or intermediate-risk PCa and those with low-risk PCa [21, 22]. Furthermore, ADC maps can distinguish between GS 3 + 4 and 4 + 3 [23, 24]. Alessandrino et al.[23] observed a significant difference in the mean tumor ADC value and ADC ratio between GS 3 + 4 and 4 + 3 tumors among 119 PCa patients who underwent RP. However, the results show great variations depending on different ADC measurement values and different parameters used. Consistent with prior studies, our findings revealed that GS 3 + 4 tumors exhibited significantly higher mean ADC values compared to GS 4 + 3 tumors. Nevertheless, additional investigation is warranted to enhance the discriminative capacity of ADC parameters in distinguishing between these two GS groups.
There can be variations between the GS identified in a biopsy and that observed in a surgical specimen, with documented rates of upgrading reaching up to 40% [25, 26]. Therefore, using functional imaging techniques could ease worries about upgrading GS from needle biopsy to RP samples. Previous studies have demonstrated the utility of multiparametric MRI (mpMRI) in prognosticating GS upgrading in PCa patients with a GS of 3 + 4 [27–29]. Rozenberg et al.[27] observed that 26% of patients in their cohort experienced a post-RP upgrade to GS 4 + 3. Their investigation emphasized the significance of employing ADC texture analysis for predicting such upgrades. Similarly, Kim et al.[29] analyzed a cohort of 539 patients with biopsy-proven GS 3 + 4 and reported a 35.3% rate of GS upgrading after RP. Their findings underscored the pivotal role of mpMRI in predicting postoperative GS upgrades specifically in GS 3 + 4 PCa cases. In this current study, we identified a significant dose-response correlation between tumor ADC values and disease progression in our entire patient cohort, including those with GS 3 + 4. We found that lower tumor ADC values were associated with a higher risk of disease progression in patients with GS 3 + 4 tumors, suggesting a possible upgrade in GS for these patients. Therefore, since patients undergoing definitive RT were assessed using biopsy-confirmed GS, incorporating tumor ADC values is crucial for predicting treatment outcomes, particularly in cases involving GS 3 + 4 tumors.
Previous studies demonstrated that tumor ADC values have been correlated with the rate of BR in patients with localized PCa who were treated with either RP [10] or definitive RT [12, 30, 31]. In a study involving 51 patients treated with external beam RT and/or brachytherapy, Chatterjee et al.[31] observed a significantly lower tumor ADC values in patients with BR compared to those who did not (0.78 ± 0.17 vs. 0.96 ± 0.26 µm²/ms, p = 0.04). Similarly, Yamaguchi et al.[30] demonstrated in an independent study of 86 PCa patients treated with definitive RT that a tumor ADC ratio of < 0.59 µm²/ms and a Gleason score ≥ 8 served as independent predictors of increased BR risk. In our recent study involving 503 PCa patients treated with RT, we observed that patients who had progression had a lower mean tumor ADC value compared to those who did not (0.712 ± 0.158 vs. 1.365 ± 0.227 × 10−3 mm²/sec; p < 0.001) [12]. Furthermore, there was a significant difference in the 5-year freedom from biochemical failure rates (96.3% vs. 90%; p < 0.001) and progression-free survival rates (83.8% vs. 73.5%; p = 0.002) between patients with higher and lower mean ADC values. Our study revealed a significant difference in tumor ADC values between patients who experienced disease progression and those who did not. Patients with high tumor ADC values had higher rates of bDFS compared to those with low tumor ADC values. However, there was no significant difference in PCSS between the two groups, possibly due to the limited follow-up time. Thus, a more extended period of follow-up is necessary to more accurately evaluate the survival outcomes.
Our study has limitations, with the most significant being its retrospective nature and potential for selection bias. Specifically, we analyzed patients who underwent definitive RT, ensuring they had biopsy-confirmed GS. This may not fully reflect the GS identified in RP specimens, complicating the precise assessment of GS upgrading. Secondly, there might be errors in calculating the ADC because ROIs were placed manually. To minimize this, each measurement was repeated twice, and an average was taken. We also checked for consistency in defining these regions, finding interobserver good agreement for both ROI definition and ADC measurements. Finally, ADC measurements were conducted using various magnetic field strengths, including 1.5-T and 3-T, with different b values. Nevertheless, previous research has shown that ADC values are not significantly influenced by magnetic field strength, and our findings, along with others', support this assertion [32, 33]. Despite these limitations, our study holds significance in demonstrating the predictive value of tumor ADC values for treatment outcomes in a larger patient cohort subjected to consistent treatment protocols and adequate follow-up.